[unreadable] Aseptic loosening has become the major complication of total joint replacement, with an incidence of as high of 34%. Our long-term goal is to develop therapeutic approaches to prevent or retard the process of aseptic loosening of prosthetic joint. Our hypothesis is that wear debris-associated inflammation and osteolysis are separate but related mechanisms in the periprosthetic tissue, and both anti-inflammatory therapy and antiosteolytic therapy are required to inhibit aseptic loosening. Delivery of the generally short half-life therapeutic agents to the loosening prosthetic joint is highly problematic. Gene therapy, though still in its infancy, provides attractive avenue for targeted delivery and sustained expression of therapeutic protein(s). The objective of this proposal is to validate a murine long-term model of a prosthetic joint failure due to wear debris stimulation for the evaluation of combination gene therapy against inflammation and osteolysis. This will be accomplished by pursuing the following specific aims: (1) to characterize the biomechanical and pathological aspects of a longterm mouse model of debris-associated bone resorption and joint prosthesis failure; (2) to evaluate the efficacy of combination anti-inflammatory and anti-osteolytic gene therapy in preventing or treating debris-associated implant loosening; and (3) to examine the influence and cell trafficking of a cell-gene (ex vivo) therapy, and compare it with in vivo gene transfer on the aspects of transgene expression and dissemination, long-term effectiveness, and potential adverse effects. The successful outcome of the study will validate a useful tool for the investigation of aseptic loosening, and lay important foundations for virus-mediated gene delivery of therapeutic proteins, especially OPG in combination with pro-inflammatory cytokine blockers, as a promising therapeutic regimen for debris-associated prosthetic loosening. [unreadable] [unreadable] [unreadable] [unreadable]